August 23, 2012

More mutations in children of older fathers, and how it relates to human origins

Most of the coverage of the new Kong et al. paper has focused on the rising risk for inheritable diseases such as autism and schizophrenia in the children of older fathers. And, indeed, that is is the larger story, and, perhaps, the more useful one for society.

But, for those of us interested in the origins of our species, there is another story:

We show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20 × 10−8 per nucleotide per generation.

This mutation rate is in line with other direct measured rates, and is about twice smaller than the widely used 2.5x10^-8 rate used in evolutionary studies. Application of the low rate has led to a much older Human-Chimp divergence than was previously thought. That, in turn, will make mitochondrial Eve much older, because the mtDNA clock is calibrated on the Human-Chimp divergence. Practically every study of the last 10 years that looked at human origins and used the 2.5x10^-8 rate needs to be dusted off and made up to date.

But there is yet another story. The beauty of the Langergraber et al. paper is that it inferred the Human-Chimp divergence on the basis of directly observed quantities: mutation rates and generation times. But, there was one quantity which they could not measure directly: the mutation rate in the apes. Thus, they used the mutation rate of humans for the apes as well; that is very reasonable, because presumably the same underlying chemical machinery affects the rate in humans and their simian friends. But, here's where things get complicated:

Mean human paternal ages are about ~7 years older than chimp ones, and ~10 years older than gorilla ones. What this means, is that on average, younger chimp dads and younger gorilla dads have babies. But, the new Kong et al. paper:

Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years.

A back-of-the envelope calculation suggests that the higher age of human fathers may contribute ~30-50% more mutation in humans than in chimps/gorillas. Conversely, the mutation rate used for chimps should not be the human one: it should be even lower.

What are the implications of this?

The divergence of Humans from Chimps has been estimated by summing up mutations on two branches to their most recent common ancestor (MRCA). Younger chimp fathers = lower mutation rate / generation = Chimp-to-MRCA branch just got older.

In other words, just as we learned than humans diverged from chimps ~7-13 million years ago, it may be that they did so even earlier.

Nature 488, 471–475 (23 August 2012) doi:10.1038/nature11396

Rate of de novo mutations and the importance of father’s age to disease risk

Augustine Kong et al.

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent–offspring trios at high coverage. We show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20???10?8 per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5?years. After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.

14 comments:

That's quite interesting, it breaks even my own notions on the matter which, rather consistently, pointed to a 8-10 Ka ago for the Pan-Homo divergence.

I'm surprised but mostly intrigued about that "even earlier" - and what implications it may have on the human-specific molecular-clock-o-logy. Is it possible that we end up with something close to an accurate "molecular clock"? We'll see.

I'm not sure you can conclude that the mutation rate should be lower in chimps because of their shorter generation time... If the mutation rate is linear in the father's age (and most mutations by far are from the father), then mutation rate scales in years not in generations.

The chimps might have fewer mutations per generation, but they have more generations per unit of time.

Assuming, of course, that the mutation rate in humans is even applicable to the other apes, which we don't know yet is true.

Since the mutation rate in Homo and Pan is known (well, estimated in the case of Pan, but let's play along), their generation lengths are known, and the sequence divergence between them is known, then the lowering of the Pan rate (/gen) means that the MRCA-Homo branch must be responsible for a bigger share of the (known) divergence between Homo and Pan. But, since generation length is fixed, that means more human generations => older MRCA.

I am wondering how this data on the ages of fathers, at for argument sake, the conception of their first child applies into the past. In my country, Australia, the age of fathers at the birth of their first child is over 30 years yet their own fathers were younger at the birth of their first child, and their grandfathers younger still. I am also thinking about the age of fathers at times when the age of men at mortality was between 40 and 50. Longevity has changed many things including the age of fatherhood.

Looking at figure 2 of the paper, I would say a linear fit is fine for the mutation rate as a function of age. I'm not sure the exponential fit is much better (the text doesn't really say, unless I missed it, and I haven't read the supplemental material yet).

As for knowing the Pan mutation rate, I am not so sure. I find it quite likely that it is close to humans, but we don't know from direct evidence yet, and it could be higher (closer to the 1e-9 we often see used) if humans had a slow down in mutation rate quite recently. I don't think this is the case, I'm just saying that we don't know right now (but I know of several studies that will look into it, so we probably will know very soon).

Even if the mutation rate scales linearly with paternal age, I think a lower Pan rate (/gen) will lead to an older Pan-Homo common ancestor.

The sequence divergence between Pan and Homo is known (directly measured). Part of it accumulated on the MRCA-to-Homo branch, and part of it on the MRCA-to-Pan branch.

If the mutation rate (/gen) for Homo and Pan is the same (the hypothesis of the Langergraber et al. paper), and given that Pan generations are shorter than human ones, this means that of the total Homo-Pan sequence divergence, a bigger chunk accumulated on the MRCA-to-Pan branch.

But, now that the Pan mutation rate (/gen) appears lower, this means that the share of the divergence that has accumulated on the MRCA-to-Pan branch is reduced, and the share that has accumulated on the MRCA-to-Homo branch is increased.

Since it now appears that more genetic divergence accumulated on the MRCA-to-Homo branch, and given that we know human mutation rate and human generation length => more human generations to MRCA => more calendar years to MRCA.

So, I do think the MRCA will get older, regardless of how the Pan rate may be adjusted (linearly or not) due to younger Pan dads. The fact that it will be smaller suffices.

Of course direct measurement of the Pan rate will clarify things further. But, whenever that comes along, we must be careful, because if they're lamb chimps they may not have generation lengths similar to those recorded from observation on wild chimps.

More data please. No reason to think the Icelandic rate of mutation will be 1:1 everywhere across the species. And given all the papers about testes size, societies and mating patterns of mammals and the ape family, the rate of mutation per year of sperm life for chimps and the ancestors of chimps and humans is still a guess. I think you have already written about the compression of evolutionary age due to the number and size of population explosions and successive collapses. The mutation rate is not just some function of the number of linear years or direct generations. The total mutations in survivors of collapses is a sampling problem as well. Sometimes they will have fewer mutations, sometimes more. Old mother nature is shaking the tree.

Mutation rate increases are a product of the aging process - the same sort of processes that drive cancer (which is basically an instance of cells in the body mutating rather than reproducing their parents accurately) and other biochemical breakdowns in the bodies of the elderly. To predict expected mutation rates between humans and other species accurately, you need to be looking at it in terms of age years, and not absolute numbers of years.

The place where there is real grounds for concern about the accuracy of mutation rates is not so much in non-hominin primates and Paleolithic hominins, since the life expectencies for them over the millenia have probably been pretty consistent given the generally consistent social structures (maybe there is a slight bump towards advanced paternal age at the Upper Paleolithic Revolution). The area where I would most doubt that accuracy of long term calibrations based on advanced paternal age effects is the Neolithic and beyond, where the age distribution of fathers relative to prior eras may have changed materially, although much of that change has been only in the last couple of centuries.

It may be possible the replication process has some basal mutation rate, so the mutation rate for chimps (who overall have much younger fathers) would not necessarily have a correspondingly much lower mutation rate.

Sexual maturity is reached between 8 and 10 years in chimps. Arguably about 5 years earlier than in humans. If we assume that humans and chimps have a similar mutation rate when they reach sexual maturity, then the difference in mutation rate would have to be more similar than infered from the absolute 7 years different.It is likely as well, that humans in pre-modern times conceived earlier than those statistics suggests.This leads me to think that the chimp to human difference in mutation rate at time of conception is probably not so significant.

Puberty at 15? Not normal. Per Wikipedia and in my experience: "usually, puberty begins between 10 and 13 years of age", that is 2-3 years after chimps.

In very extreme cases some girls have become pregnant (and given birth) as early as 5 y.o.: http://en.wikipedia.org/wiki/Lina_Medina

The anthropological literature however suggest that motherhood is rare before the age of 15 or later and that average generation length tends to be between 25-30 years, varying, sometimes notably, depending on cultures and also somewhat depending on gender.

Now, which is the actual generation length in chimpanzees? Seven years earlier than humans according to the paper, that means that it's c. 20 years.

Separately, the process of growing and getting old is different in humans and chimps and I would expect this also to affect sperm development. The matter, specially in chimps, must be observed and studied and not so much speculated about.

I would say a linear fit is fine for the mutation rate as a function of age.

I have argued this for years and it has fallen on deaf ears. Generation lengths are simply mute, because mutations are mostly carried by males, and are time-dependent. Thus, mutations per time is the appropriate measure, and generation length drops out. In other words, whether you assume a generation length of 20 years or 40 years - the mutation rate per time remains the same and remains the only factor.

Puberty in girls is getting early. It used to start at 15 plus in relatrively recent times. Its not clear if this change is due to nutrition, hormone exposure or some kind of genetic/maternal diet effect.

It is possible that similar effects are occuring in boys. Also I doubt in a patriarchal society a young male would have much access. Although high male mortality could also work in favour of access.

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